9-substituted-8-oxo-adenine compounds as toll-like receptor (tlr7 ) modulators

ABSTRACT

The present invention provides compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , Y 1 , X 1 , L and R 2  are as defined in the specification, and pharmaceutically acceptable salts thereof, as well as processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The present invention relates to adenine derivatives, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy.

The immune system is comprised of innate and acquired immunity, both ofwhich work cooperatively to protect the host from microbial infections.It has been shown that innate immunity can recognize conservedpathogen-associated molecular patterns through toll-like receptors(TLRs) expressed on the cell surface of immune cells. Recognition ofinvading pathogens then triggers cytokine production (includinginterferon alpha(IFNα)) and upregulation of co-stimulatory molecules onphagocytes, leading to modulation of T cell function. Thus, innateimmunity is closely linked to acquired immunity and can influence thedevelopment and regulation of an acquired response.

TLRs are a family of type I transmembrane receptors characterized by anNH₂-terminal extracellular leucine-rich repeat domain (LRR) and aCOOH-terminal intracellular tail containing a conserved region calledthe Toll/IL-1 receptor (TIR) homology domain. The extracellular domaincontains a varying number of LRR, which are thought to be involved inligand binding. Eleven TLRs have been described to date in humans andmice. They differ from each other in ligand specificities, expressionpatterns, and in the target genes they can induce.

Ligands which act via TLRs (also known as immune response modifiers(IRMS)) have been developed, for example, the imidazoquinolinederivatives described in U.S. Pat. No. 4,689,338 which include theproduct Imiquimod for treating genital warts, and the adeninederivatives described in WO 98/01448, WO 99/28321 and WO 2007/034882.

This patent application describes a class of 9-substituted-8-oxoadeninecompounds having immuno-modulating properties which act via TLR7 thatare useful in the treatment of viral or allergic diseases and cancers.

In accordance with the present invention, there is therefore provided anadenine compound represented by Formula (I):

wherein

-   -   R¹ represents hydrogen, hydroxyl, C₁-C₆ alkoxy, C₂-C₅        alkoxycarbonyl, or a C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl or C₃-C₈        cycloalkyl group, wherein any available carbon atom in each        group is optionally substituted by one or more substituents        independently selected from halogen, hydroxyl, C₁-C₆ alkyl,        C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₅        alkoxycarbonyl, amino, mono or di-C₁-C₆ alkylamino;    -   Y¹ represents a single bond or C₁-C₆ alkylene;    -   X¹ represents a single bond or an oxygen or sulphur atom,        sulphinyl (SO), sulphonyl (SO₂) or NR⁴ where R⁴ is hydrogen or        C₁₋₆alkyl;        provided that when R¹ is hydroxyl, C₁₋₆alkoxy or C₂-C₅        alkoxycarbonyl and X¹ is oxygen, Y₁ is other than a single bond;    -   L is a bond or a straight or branched C₁₋₆alkylene group,        wherein up to 3 carbon atoms within the alkylene group may be        replaced by oxygen, sulfur, SO, SO₂, carbonyl or NR⁵ wherein R⁵        is hydrogen or C₁₋₆alkyl; and    -   R² is either a saturated or partially unsaturated 4-8 membered        heterocycle comprising 1 or 2 hetero atoms selected from        nitrogen, oxygen and sulphur, provided that at least one of the        heteroatoms is nitrogen, which heterocycle is optionally        substituted by one or more groups selected from halogen,        hydroxyl, oxo, C₁₋₆alkoxy, C₂₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl,        carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl,        C₁₋₆alkylsulfinyl or an C₁₋₆ alkyl group wherein from 1 to 3        carbon atoms are optionally replaced by oxygen, sulphur, SO,        SO₂, carbonyl or a group NR³ where R³ is hydrogen or C₁₋₆alkyl;    -   or R² is a group of sub formula (i)

-   -   where R⁶ is hydrogen or C₁₋₆alkyl;    -   R⁷ is hydrogen, or C₁₋₆alkyl;    -   R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, a        C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₃-C₈ cycloalkyl or a 3-8        membered saturated or partially saturated heterocyclic ring        wherein each group may be optionally substituted by one or more        groups selected from halogen, cyano, S(O)_(m)R¹⁰, OR¹⁰, C(O)R¹⁰,        CO₂R¹⁰, OC(O)R¹⁰, SO₂NR¹¹R¹², CONR¹¹R¹², NR¹¹R¹², NR¹¹SO₂R¹⁰,        NR¹¹CO₂R¹⁰, NR¹¹COR¹⁰, where any C₁-C₆ alkyl, C₂-C₆ alkenyl,        C₂-C₆ alkynyl or C₃-C₈ cycloalkyl groups R⁸ may also be        optionally substituted by one or more C₆-C₁₀ aryl, C₅-C₁₀        heteroaryl, a 3-8 membered saturated or partially saturated        heterocyclic ring or C₃-C₈ cycloalkyl groups and where any        C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl groups R⁸ may also be        optionally substituted by one or more C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl groups, and where any        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl        group, a C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl or 3-8 membered        saturated or partially saturated heterocyclic ring substituents        are optionally substituted by one or more groups independently        selected from halogen, cyano, S(O)_(m)R¹³, OR¹³, C(O)R¹³,        CO₂R¹³, OC(O)R¹³, SO₂NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴R¹⁵, NR¹³SO₂R¹³,        NR¹⁴CO₂R¹³ or NR¹⁴COR¹³ groups;    -   or R⁷ and R⁸ may be combined together with adjacent carbon atom        to form a 3-8 membered saturated carbocycle or a 3-8 membered        saturated or partially saturated heterocycle optionally        substituted by one or more groups independently selected from        halogen, cyano, S(O)_(m)R¹³, OR¹³, C(O)R¹³, CO₂R¹³, OC(O)R¹³,        SO₂NR¹⁴R¹⁵, CONR¹⁴R¹⁵, News, NR¹³SO₂R¹³, NR¹⁴CO₂R¹³ or NR¹⁴COR¹³        groups;    -   R⁹ is hydrogen, S(O)_(m)R¹⁶, C(O)R¹⁶, SO₂NR¹⁷R¹⁸, CONR¹⁷R¹⁸,        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl        group, the latter four groups being optionally substituted by        one or more substituents independently selected from halogen,        cyano, S(O)_(m)R¹⁹, OR¹⁹, C(O)R¹⁹, OC(O)R¹⁹, CO₂R¹⁹, SO₂NR²⁰R²¹,        CONR²⁰R²¹, NR²⁰R²¹, NR²⁰SO₂R¹⁹, NR²⁰CO₂R¹⁹ or NR²⁰COR¹⁹;    -   where m is 0, 1 or 2,        provided that when R⁸ is a C₆-C₁₀ aryl or a C₈-C₁₀ heteroaryl,        R⁹ is not hydrogen or unsubstituted C₁-C₆ alkyl,        and provided that when R⁷ and R⁹ are hydrogen or C₁-C₆ alkyl,        then R⁸ is other than C₁-C₆ alkyl mono-substituted by C₆-C₁₀        aryl or a C₅-C₁₀ heteroaryl;    -   wherein R¹⁰, R¹³, R¹⁶ and R¹⁹ are independently selected from        hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃-C₈        cycloalkyl, a C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group, which to        may be optionally substituted on any available carbon atom by        one or more groups selected from halogen, hydroxyl, cyano,        C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio, C₁₋₆alkylsulphonyl,        carboxy, C₁₋₆alkylcarbonyloxy, sulphamoyl, C₁₋₆alkylsulphamoyl,        di-C₁₋₆alkylsulphamoyl, carbamoyl, C₁₋₆alkylcarbamoyl,        di-C₁₋₆alkylcarbamoyl, amino, C₁₋₆alkylamino or        di-C₁₋₆alkylamino;    -   R¹¹, R¹², R¹⁴, R¹⁵, R¹⁷, R¹⁸, R²⁰ or R²¹ are independently        selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl,        C₃-C₈ cycloalkyl, a C₆-C₁₀ aryl or C₈-C₁₀ heteroaryl group,        which may be optionally substituted on any available carbon atom        by one or more groups selected from halogen, hydroxyl, cyano,        C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio, C₁₋₆alkylsulphonyl,        carboxy, C₁₋₆alkylcarbonyloxy, sulphamoyl, C₁₋₆alkylsulphamoyl,        di-C₁₋6alkylsulphamoyl, carbamoyl, C₁₋₆alkylcarbamoyl,        di-C₁₋₆alkylcarbamoyl, amino, C₁₋6alkylamino or        di-C₁₋₆alkylamino;    -   or R¹¹ and R¹², R¹⁴ and R¹⁵, R¹⁷ and R¹⁸ or R²⁰ and R²¹ together        with the nitrogen atom to which they are attached form a 3- to        8-membered saturated heterocyclic ring comprising a ring        nitrogen atom and optionally one or more further heteroatoms        independently selected from nitrogen, oxygen, sulphur and        sulphonyl, the heterocyclic ring being optionally substituted by        one or more substituents independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃-C₈ cycloalkyl, halogen, hydroxyl,        cyano, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulphonyl sulphamoyl,        C₁₋₆alkylsulphamoyl, di-C₁₋₆alkylsulphamoyl, carbamoyl,        C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, amino,        C₁₋₆alkylamino, di-C₁₋₆alkylamino, amido, or a group NR³⁴CO₂R³⁵        or NR³⁴COR³⁵ where R³⁴ and R³⁵ are independently selected from        hydrogen and C₁₋₆alkyl;        or a pharmaceutically acceptable salt thereof.

In the context of the present specification, unless otherwise stated, analkyl substituent group or an alkyl moiety in a substituent group may belinear or branched. They may for example contain from 1 to 6 carbonatoms. Examples of C₁-C₆ alkyl groups/moieties include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl andn-hexyl. Similarly, an alkylene group/moiety may be linear or branched.Examples of C₁-C₆ alkylene groups/moieties include methylene, ethylene,n-propylene, n-butylene, n-pentylene, n-hexylene, 1-methylethylene,2-methylethylene, 1,2-dimethylethylene, 1-ethylethylene,2-ethylethylene, 1-, 2- or 3-methylpropylene and 1-, 2- or3-ethylpropylene. An alkenyl or alkynyl group is an unsaturated linearor branched group, containing for example from 2 to 6 carbon atoms.

Cycloalkyl or carbocycle groups are rings containing, for example, from3 to 8 carbon atoms and are saturated.

Heterocyclic groups are rings which may be saturated, partiallyunsaturated or unsaturated, and contain from 3 to 20 atoms, at least oneand suitably from 1 to 4 atoms are heteroatoms selected from oxygen,sulphur and nitrogen. Rings may be monocyclic, fused, bridged, or spirobicyclic heterocyclic ring system(s). Monocyclic heterocyclic ringscontain from about 3 to 12 ring atoms, with from 1 to 5 heteroatomsselected from N, O, and S, and suitably from 3 to 7 member atoms, in thering. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably7 to 12 member atoms, in the ring. Bicyclic heterocycles contain fromabout 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms.Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ringsystems.

For the avoidance of doubt, rings which are described as being“partially unsaturated” may contain one or more multiple bonds but theyare not aromatic in nature.

Examples of heterocyclic groups which are saturated or partiallysaturated include cyclic ethers (oxiranes) such as ethyleneoxide,tetrahydrofuran, dioxane, and substituted cyclic ethers. Heterocyclescontaining nitrogen include, for example, azetidine, pyrrolidine,piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and thelike. Typical sulfur containing heterocycles includetetrahydrothiophene, dihydro-1,3-dithiol-2-yl, andhexahydrothiepin-4-yl. Other heterocycles include dihydro-oxathiol-4-yl,tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl,tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl,morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl,octahydrobenzofuranyl, octahydrobenzimidazolyl, andoctahydrobenzothiazolyl. For heterocycles containing sulfur, theoxidized sulfur heterocycles containing SO or SO₂ groups are alsoincluded. Examples include the sulfoxide and sulfone forms oftetrahydrothiophene. A suitable value for a heterocyclyl group whichbears 1 or 2 oxo or thioxo substituents is, for example,2-oxopyrrolidinyl, to 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl,2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl,2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.

Heterocyclic groups which are aromatic in nature are referred to as“heteroaryl” groups. These groups are aromatic mono-, bi-, or polycyclicheterocyclic ring incorporating one or is more (for example 1-4)heteroatoms selected from N, O, and S. The term heteroaryl includes bothmonovalent species and divalent species. Examples of heteroaryl groupsinclude furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl,pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl,purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl,quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl,phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl,2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl,1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl,pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl,imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl” also covers ring systemswherein at least one ring is an aromatic ring containing 1 or moreheteroatoms selected from O, S and N and one or more of the other ringsis a non-aromatic, saturated or partially unsaturated ring optionallycontaining one or more heteroatoms selected from O, S and N, for example1,2,3,4-tetrahydro-1,8-naphthyridinyl,1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

Preferably R¹ represents hydrogen.

In a particular embodiment, Y¹ represents unsubstituted C₁₋₆alkylenesuch as a linear C₁₋₆alkylene for instance methyl, ethyl, propyl,n-butyl, n-pentyl or n-hexyl. In particular, R¹ is n-butyl

Particular examples of X¹ groups are oxygen, sulphur, or NR⁴, where R⁴is as defined above. When X¹ is a NR⁴ group, suitable R⁴ groups includehydrogen or methyl, and in particular hydrogen.

In a further embodiment, X¹ represents oxygen.

Where any of the carbon atoms within the L group are replaced by oxygen,sulfur, SO, SO₂, carbonyl or NR⁵, these are suitably arranged at anintermediate position in the alkylene chain so that the terminal atomsof L are carbon.

Where L contains an NR⁵ group, R⁵ is suitably hydrogen or C₁₋₆alkyl suchas hydrogen or methyl. In a particular embodiment, up to 2 carbon atomswithin the alkylene group of L may be replaced by oxygen, sulfur, SO,SO₂, carbonyl or NR⁵. In a further particular embodiment, no more thanone carbon atom within L is replaced by oxygen, sulfur, SO, SO₂,carbonyl or NR⁵.

In a particular embodiment, L is a bond or a straight or branchedC₁₋₆alkylene, and in particular a straight chain alkylene such asn-propylene.

In another embodiment, L is an alkylene chain wherein two carbon atomsare replaced, one by a carbonyl group and one by a group NR⁵.

In a further embodiment, R² is a saturated or partially unsaturated 4-8membered heterocycle comprising 1 or 2 heteroatoms selected fromnitrogen, oxygen and sulphur, provided that at least one of theheteroatoms is nitrogen, which may be optionally substituted asdescribed above. In particular, R² is pyrrolidine, piperidine,piperidine, morpholine, thiomorpholine, thiomorpholine-1-oxide orthiomorpholine-1,1-dioxide.

Suitably R² is a saturated nitrogen containing heterocycle such aspyrrolidinyl or morpholine.

In a particular embodiment, the ring R² is linked to the group L by wayof a ring nitrogen atom.

The ring R² may be unsubstituted.

Alternatively the ring R² may carry one or more substituents, forexample from one to three substituents independently selected fromhalogen, hydroxyl, oxo, C₁₋₆alkoxy, C₂₋₆-alkylcarbonyl,C₁₋₆alkylsulfonyl, carbamoyl, C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl,C₁₋₆alkylsulfinyl or a C₁₋₆ alkyl group wherein from 1 to 3 carbon atomsare optionally replaced by oxygen, sulphur, SO, SO₂, carbonyl or a groupNR³ where R³ is hydrogen or

In particular, when R² is a ring, it is optionally substituted by one ortwo oxo groups.

A further example of a suitable substituent for R² is an alkyl groupwhich is optionally interposed with an oxygen atom, so as to form aalkoxyalkyl group such as a C₁₋₃ alkoxyC₁₋₂alkyl group, for instancemethoxymethyl.

Another suitable substitutent for a ring R² is di-C₁₋₆alkylcarbamoyl,such as dimethylcarbamoyl.

In another embodiment R² is a group of sub formula (i)

where R⁶, R⁷, R⁸ and R⁹ are as defined above.

In particular, R⁶ and R⁷ are independently hydrogen or C₁₋₃ alkyl.

For instance, R⁶ is hydrogen or methyl.

In a further embodiment, R⁷ is hydrogen or methyl

Suitably, R⁸ is hydrogen or C₁₋₆alkyl which may be optionallysubstituted as defined above, such as optionally substituted methyl.

In a particular embodiment, R⁸ is hydrogen or a C₁₋₆ alkyl optionallysubstituted by one or more groups selected from C₂₋₅ alkoxycarbonyl,carboxy, hydroxy, amino optionally substituted by one or two C₁₋₆ alkylgroups which may be the same or different, carbamoyl optionallysubstituted by one or two C₁₋₆ alkyl groups which may be the same ordifferent 6-10 membered aryl optionally substituted by halogen, hydroxy,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or aminooptionally substituted by one or two C₁₋₆ alkyl groups which may be thesame or different.

For example R⁸ is a C₁₋₆alkyl group substituted by C₁₋₆ alkoxy such asmethoxy.

Particular examples of R⁹ include hydrogen or a CONR¹⁷R¹⁸ where R¹⁷ andR¹⁸ are as defined above. In particular, R¹⁷ and R¹⁸ are C₁₋₆ alkylgroups such as methyl, or R¹⁷ and R¹⁸ together with the nitrogen atom towhich they are attached form a a 3- to 8-membered saturated heterocyclicring comprising a ring nitrogen atom and optionally one or more furtherheteroatoms independently selected from nitrogen, oxygen, sulphur andsulphonyl, such as a morpholine ring.

Examples of compounds of the invention include:

-   6-Amino-2-butoxy-9-(3-pyrrolidin-1-ylpropyl)-7,9-dihydro-8H-purin-8-one;-   1-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N,N-dimethyl-L-prolinamide;-   6-Amino-2-butoxy-9-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}-7,9-dihydro-8H-purin-8-one;-   N²-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N¹,N¹,N²-trimethylglycinamide;-   1-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]pyrrolidine-2,5-dione;-   6-Amino-2-butoxy-9-(3-{[(1S)-2-methoxy-1-methylethyl]amino}propyl)-7,9-dihydro-8H-purin-8-one;    and-   6-Amino-2-butoxy-9-{3-[methyl-(2-morpholin-4-yl-2-oxo-ethyl)-amino]-propyl}-7,9-dihydro-purin-8-one,    and pharmaceutically acceptable salts thereof.

The present invention further provides a process for the preparation ofa compound of formula (I) or a pharmaceutically acceptable salt thereofas defined above which comprises reacting a compound of formula (II)

wherein X¹, Y¹and L are as defined in formula (I), and Z is a leavinggroup, with a compound of formula (III)

H—R²  (III)

where R² is as defined in relation to formula (I), except that where R²is a substituted or unsubstituted saturated or unsaturated 4-8 memberedheterocycle, it is linked to the H group of formula (III) by way of anitrogen atom.

Suitable leaving groups Z are halogen atoms such as bromine, orchlorine, as well as mesylate and tosylate. The reaction is suitablycarried out in an organic solvent such as dimethylsulphoxide (DMSO),acetonitrile or N,N-dimethylformamide for example, using an excess ofthe amine, preferably at moderate to elevated temperature, e.g. at atemperature in the range from 0 to 150° C. The reaction may be conductedin the presence of a base such as an alkali metal carbonate (e.g. sodiumcarbonate or potassium carbonate).

Compounds of formula (II) may be prepared as illustrated in thefollowing reaction scheme:

The compound of formula (B) is prepared by reacting the compound offormula (A) with ammonia in an organic solvent such as methanol,ethanol, propanol, butanol, tetrahydrofuran, 1,4-dioxane, diglyme,acetonitrile or an aqueous mixture of any one of the preceding solvents.The reaction may be carried out in an autoclave, and at a temperature,for example, in the range from 20 to 200° C.

Compounds of formula (C) may be prepared by reacting the compound offormula (B) with an alkanol in the presence of a base such as sodiumhydride or potassium t-butoxide and in an organic solvent such astetrahydrofuran, 1,4-dioxane, diglyme, N,N-dimethylformamide ordimethylsulfoxide, preferably at elevated temperature, e.g. at atemperature in the range from 20 to 150° C. Alternatively an alkalimetal such as sodium may be dissolved in the alkanol and then reactedwith the compound of formula (B), preferably at elevated temperature,e.g. at a temperature in the range from 20 to 150° C.

Compounds of formula (D) are prepared by brominating a compound offormula (C). The to reaction may be carried out using a brominatingagent such as bromine, hydroperbromic acid or N-bromosuccinimide (NBS),in an organic solvent such as carbon tetrachloride, methylene chloride,dichloroethane, diethyl ether, acetic acid or carbon disulfide. Thereaction temperature will generally be in the range from 0° C. to theboiling point of the solvent.

Compounds of formula (E) are prepared by reacting a compound of formula(D) with sodium methoxide in an organic solvent such as methanol and ata temperature, for example, in the range from 20 to 150° C.

Compounds of formula (F) may be obtained by treating a compound offormula (E) with an acid such as trifluoroacetic acid in an organicsolvent such as methanol.

Compounds of formula (G) are prepared by reacting a compound of formula(F) with a compound of formula Z-L-Z wherein L is as defined in relationto formula (I) and each Z is a leaving group such as a halogen, mesylateor triflate. The reaction may be carried out in an organic solvent suchas N,N-dimethylformamide, dimethylsulfoxide or acetonitrile with a basepresent, preferably at room temperature (20° C.). A base such as analkali metal carbonate, e.g. sodium carbonate or potassium carbonate; analkaline earth metal carbonate, e.g. calcium carbonate; a metalhydroxide, e.g. sodium hydroxide or potassium hydroxide; a metalhydrogenate, e.g. sodium hydride; or a metal alkoxide, e.g. potassiumt-butoxide, may be used.

Compounds of formula (II) may be obtained by treatment of a compound offormula (G) with an acid. The reaction may be carried out in an organicsolvent such as methanol using either an inorganic acid such ashydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acidsuch as trifluoroacetic acid.

Alternatively, compounds of formula (I) may be prepared by reacting acompound of formula (IV)

where L, R², R¹, X¹ and Y¹ are as defined in relation to formula (I) andR³⁸ is a C₁₋₄alkyl group such as methyl, with an acid which is either aninorganic acid such as hydrochloric acid, hydrobromic acid or sulfuricacid, or an organic acid such as trifluoroacetic acid. The reaction maybe carried out in an organic solvent such as methanol.

Compounds of formula (IV) may be prepared by reacting a compound offormula (IVA)

wherein L, R², R¹, X¹ and Y¹ are as defined in relation to formula (I),and R³⁸ is as defined in relation to formula (IV), with a compound offormula (V)

Z-L-R²  (V)

wherein L and R² are as defined in relation to formula (I) and Z is aleaving group such as a halogen, mesylate or triflate. Reactionconditions are similar to those described above for the reaction of thecompound of formula G to form the compound of formula II above.

Compounds of formula (IVA) are analogous to compound G above and can beprepared using analogous methods.

In an alternative embodiment, compounds of formula (I) may be preparedby reacting a compound of formula (VI)

where R² and L are as defined in relation to formula (I) and Z¹ is aleaving group such as halogen, in particular chlorine, with a compoundof formula (VII)

R¹—Y¹—X¹—H  (VII)

where R¹, Y₁ and X¹ are as defined in relation to formula (I). Thereaction is suitably carried out in the presence of a base, such as analkali or alkaline earth metal carbonate or hydride, such as sodium orpotassium carbonate or hydride or an organic base such as triethylamine,in particular where X¹ is an oxygen or sulphur atom. It may be effectedin the presence of an organic solvent such as an alcohol such aspropenol or butanol, tetrahydrofuran, dimethylformamide,dimethylsulphoxide or diglyme, at elevated temperatures for example inthe range of from 50-200° C.

Compounds of formula (VI) are suitably prepared by reacting a compoundof formula (VIII)

where L and R² are as defined in relation to formula (I) and Z′ is asdefined in relation to formula (VI) with a metal alkoxide such as sodiummethoxide, following by treatment with an acid. The reaction is suitablyeffected in an organic solvent such as diethylether, tetrahydrofuran or1,4-dioxane at a temperature in the range of from 0° C. to the boilingpoint of the solvent.

Compounds of formula (VIII) can, in their turn be prepared bybromination of a compound of formula (IX)

where L and R² are as defined in relation to formula (I) and Z′ is asdefined in relation to formula (VI) using conditions analogous to thosedescribed above in relation to the preparation of compound (D).

Compounds of formula (IX) can be prepared by coupling compounds offormula (X)

where Z¹ is as defined above, with a compound of formula (V) as definedabove, using conditions broadly analogous to those described in relationto the reaction of compound (IV) and (V).

Compounds of formula (I) may also be prepared by reacting a compound offormula (XI)

where R¹, X¹, Y¹, L and R² are as defined above in relation to formula(I) using conditions similar to those described above for the conversionof a compound of formula (VIII) to a compound of formula (VI).

Compounds of formula (XI) may be prepared using for example a methodoutlined in the following scheme:

Couplings of compounds (V) and (VII) can be carried out using conditionssimilar to those described above in relation to the reactions in whichthese reagents take part.

In a further embodiment, compounds of formula (I) may be prepared by thefollowing general scheme:

where R¹, X¹, Y¹, L and R² are as defined in relation to formula (I) andZ² is a leaving group, such as halogen for example chlorine.

In this scheme, compounds of formula (I) may be prepared by reacting acompound of formula (XIV) with a compound of formula (XV) in thepresence of a base such as an alkali or alkaline earth metal carbonate,hydroxide or hydride such as sodium or potassium carbonate, hydroxide orhydride. The reaction is suitably effected in an organic solvent to suchas a halogenated hydrocarbon, for example carbon tetrachloride,chloroform etc. at a temperature in the range of from 0° C. to theboiling point of the solvent.

Compounds of formula (XIV) are suitably prepared by reacting a compoundof formula (XVII) with an appropriate cyclising agent. For example,where X¹ is amino, the cyclising is agent will be guanidine, where X¹ ishydroxyl, the cyclising agent is urea and where X¹ is mercapto, thecyclising agent is benzoyliothiocyanate. The reaction can be effected inthe presence of a base such as those described above and an organicsolvent such as THF etc. at temperatures conveniently in the range offrom room temperature to about the boiling point of the solvent.

Alternatively, compounds of formula (XVII) can be cyclised directly tocompounds of formula (I) by reaction with a compound of formula (XVI).Again the reaction may be effected in the presence of a base such asalkali or alkaline earth metal carbonate, hydroxide or hydride such assodium or potassium carbonate, hydroxide or hydride or an organic basesuch as triethylamine, diisopropylamine, pyridine or a metal alkoxidesuch as sodium methoxide. Organic solvents may be employed such astetrahydrofuan or an alkyl alcohol such as methanol or ethanol.Temperatures in the range of from room temperature to the boiling pointof the solvent may be used.

Compounds of formula (XVII) may be prepared by reacting a compound offormula (XVIII) with a compound of formula (XIX). Again the reaction issuitably effected in the presence of a base such as alkali or alkalineearth metal carbonate, hydroxide or hydride such as sodium or potassiumcarbonate, hydroxide or hydride or an organic base such astriethylamine, diisopropylamine, pyridine or a metal alkoxide such assodium methoxide. Organic solvents may be employed such astetrahydrofuan or an alkyl alcohol such as methanol or ethanol.Temperatures in the range of from 0° C. to the boiling point of thesolvent may be used.

Compounds of formula (V), (VII), (X) (XV), (XVI) (XVIII), (XIX) as wellas compounds of formula Z-L-Z described above are known compounds orthey can be prepared from known compounds by conventional methods, forexample as described in WO2005092893.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the reagents may need to be protected by protectinggroups. Thus, the preparation of the compounds of formula (I) mayinvolve, at an appropriate stage, the removal of one or more protectinggroups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3^(rd)edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt thereof, preferably an acid additionsalt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate,phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate,pyruvate, succinate, oxalate, methanesulphonate or p-toluenesulphonate.

Compounds of formula (I) are capable of existing in stereoisomericforms. It will be understood that the invention encompasses the use ofall geometric and optical isomers (including atropisomers) of thecompounds of formula (I) and mixtures thereof including racemates. Theuse of tautomers and mixtures thereof also form an aspect of the presentinvention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) and their pharmaceutically acceptable saltshave activity as pharmaceuticals, in particular as modulators oftoll-like receptor (especially TLR⁷) activity, and thus may be used inthe treatment of:

1. respiratory tract: obstructive diseases of the airways including:asthma, including bronchial, allergic, intrinsic, extrinsic,exercise-induced, drug-induced (including aspirin and NSAID-induced) anddust-induced asthma, both intermittent and persistent and of allseverities, and other causes of airway hyper-responsiveness; chronicobstructive pulmonary disease (COPD); bronchitis, including infectiousand eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis;sarcoidosis; farmer's lung and related diseases; hypersensitivitypneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis,idiopathic interstitial pneumonias, fibrosis complicatinganti-neoplastic therapy and chronic infection, including tuberculosisand aspergillosis and other fungal infections; complications of lungtransplantation; vasculitic and thrombotic disorders of the lungvasculature, and pulmonary hypertension; antitussive activity includingtreatment of chronic cough associated with inflammatory and secretoryconditions of the airways, and iatrogenic cough; acute and chronicrhinitis including rhinitis medicamentosa, and vasomotor rhinitis;perennial and seasonal allergic rhinitis including rhinitis nervosa (hayfever); nasal polyposis; acute viral infection including the commoncold, and infection due to respiratory syncytial virus, influenza,coronavirus (including SARS) and adenovirus;2. skin: psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplasticlesions; drug-induced disorders including fixed drug eruptions;3. eyes: blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune, degenerative or inflammatory disordersaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial;4. genitourinary: nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale);5. allograft rejection: acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease;6. other auto-immune and allergic disorders including rheumatoidarthritis, irritable bowel syndrome, systemic lupus erythematosus,multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison'sdisease, diabetes mellitus, idiopathic thrombocytopaenic purpura,eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndromeand Sazary syndrome;7. oncology: treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumour recurrences, and paraneoplastic syndromes;and,8. infectious diseases: virus diseases such as genital warts, commonwarts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus,molluscum contagiosum, variola, human immunodeficiency virus (HIV),human papilloma virus (HPV), cytomegalovirus (CMV), varicella zostervirus (VZV), rhinovirus, adenovirus, coronavirus, influenza,para-influenza; bacterial diseases such as tuberculosis andmycobacterium avium, leprosy; other infectious diseases, such as fungaldiseases, chlamydia, candida, aspergillus, cryptococcal meningitis,pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection and leishmaniasis.

Thus, the present invention provides a compound of formula (I) or apharmaceutically-acceptable salt thereof as hereinbefore defined for usein therapy.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for use intherapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

In particular, the compounds of the invention may be used in thetreatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis,atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterialinfections and dermatosis.

The anti-cancer treatment defined hereinbefore may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of5α-reductase such as finasteride;(iii) anti-invasion agents (for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341) andN-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), andmetalloproteinase inhibitors like marimastat, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase);(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD 1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such is as lapatinib,inhibitors of the hepatocyte growth factor family, inhibitors of theplatelet-derived growth factor family such as imatinib, inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases,inhibitors of the hepatocyte growth factor family, c-kit inhibitors, ablkinase inhibitors, IGF receptor (insulin-like growth factor) kinaseinhibitors; aurora kinase inhibitors (for example AZD1152, PH739358,VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclindependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and VEGFreceptor tyrosine kinase inhibitors such as4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO98/35985) and SUI 1248 (sunitinib; WO 01/60814), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin αvβ3 function andangiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

The invention still further provides a method of treating, or reducingthe risk of, an obstructive airways disease or condition (e.g. asthma orCOPD) which comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. For example, the dailydosage of the compound of the invention, if inhaled, may be in the rangefrom 0.05 micrograms per kilogram body weight (μg/kg) to 100 microgramsper kilogram body weight (μg/kg). Alternatively, if the compound isadministered orally, then the daily dosage of the compound of theinvention may be in the range from 0.01 micrograms per kilogram bodyweight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound/salt (active ingredient) is in association with apharmaceutically acceptable adjuvant, diluent or carrier. Conventionalprocedures for the selection and preparation of suitable pharmaceuticalformulations are described in, for example, “Pharmaceuticals—The Scienceof Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined with a pharmaceutically acceptable adjuvant,diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powderformulations, for example, formulations in the inhaler device known asthe Turbuhaler®; or systemically, e.g. by oral administration in theform of tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); or by rectal administration in the form ofsuppositories.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention (including pharmaceutically acceptable salts) may beadministered by oral or nasal inhalation. For inhalation, the compoundis desirably finely divided. The finely divided compound preferably hasa mass median diameter of less than 10 micrometres (μm), and may besuspended in a propellant mixture with the assistance of a dispersant,such as a C₈-C₂₀ fatty acid or salt thereof, (for example, oleic acid),a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated orpolyethoxylated surfactant, or other pharmaceutically acceptabledispersant.

The compounds of the invention may also be administered by means of adry powder inhaler. The inhaler may be a single or a multi dose inhaler,and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the inventionwith a carrier substance, for example, a mono-, di- or polysaccharide, asugar alcohol, or another polyol. Suitable carriers are sugars, forexample, lactose, glucose, raffinose, melezitose, lactitol, maltitol,trehalose, sucrose, mannitol; and starch. Alternatively the finelydivided compound may be coated by another substance. The powder mixturemay also be dispensed into hard gelatine capsules, each containing thedesired dose of the active compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, forexample, that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive ingredient, with or without a carrier substance, is delivered tothe patient.

For oral administration the compound of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compound of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing the compound of theinvention, the balance being sugar and a mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycontain colouring agents, flavouring agents, saccharine and/orcarboxymethylcellulose as a thickening agent or other excipients knownto those skilled in art.

The compounds of the invention may also be administered in conjunctionwith other compounds used for the treatment of the above conditions.

The invention therefore further relates to combination therapies whereina compound of the invention or a pharmaceutical composition orformulation comprising a compound of the invention is administeredconcurrently or, sequentially or as a combined preparation with anothertherapeutic agent or agents, for the treatment of one or more of theconditions listed.

In particular, for the treatment of the inflammatory diseases COPD,asthma and allergic rhinitis the compounds of the invention may becombined with agents such as tumour necrosis factor alpha (TNF-alpha)inhibitors such as anti-TNF monoclonal antibodies (for example Remicade,CDP-870 and adalimumab) and TNF receptor immunoglobulin molecules (suchas Enbrel); non-selective cyclo-oxygenase COX-1/COX-2 inhibitors whetherapplied topically or systemically (such as piroxicam, diclofenac,propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofenand ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac,azapropazone, pyrazolones such as phenylbutazone, salicylates such asaspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib,valdecoxib, lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids(whether administered by topical, oral, intramuscular, intravenous, orintra-articular routes); methotrexate, lefunomide; hydroxychloroquine,d-penicillamine, auranofin or other parenteral or oral goldpreparations.

The present invention still further relates to the combination of acompound of the invention and a leukotriene biosynthesis inhibitor,5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein(FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin;Abbott-79175; Abbott-85761; aN-(5-substituted)-thiophene-2-alkylsulfonamide;2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as isZeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinolinecompound such as L-746,530; or an indole or quinoline compound such asMK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compoundof the invention and a receptor antagonist for leukotrienes (LT B4,LTC4, LTD4, and LTE4) selected from the group consisting of thephenothiazin-3-1s such as L-651,392; amidino compounds such asCGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamidessuch as BIIL 284/260; and compounds such as zafirlukast, ablukast,montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913,iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention and a phosphodiesterase (PDE) inhibitor suchas a methylxanthanine including theophylline and aminophylline; aselective PDE isoenzyme inhibitor including a PDE4 inhibitor aninhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compoundof the invention and a histamine type 1 receptor antagonist such ascetirizine, loratadine, desloratadine, fexofenadine, acrivastine,terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine,promethazine, cyclizine, or mizolastine; applied orally, topically orparenterally.

The present invention still further relates to the combination of acompound of the invention and a gastroprotective histamine type 2receptor antagonist.

The present invention further relates to the combination of a compoundof the invention and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of acompound of the invention and an alpha-1/alpha-2 adrenoceptor agonistvasoconstrictor sympathomimetic agent, such as propylhexedrine,phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, tramazoline hydrochlorideor ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compoundof the invention and an anticholinergic agent including muscarinicreceptor (M1, M2, and M3) antagonists such as atropine, hyoscine,glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropiumbromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of acompound of the invention together with a beta-adrenoceptor agonist(including beta receptor subtypes 1-4) such as isoprenaline, salbutamol,formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,and pirbuterol.

The present invention further relates to the combination of a compoundof the invention and a chromone, such as sodium cromoglycate ornedocromil sodium.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the invention and a glucocorticoid, such as flunisolide,triamcinolone acetonide, beclomethasone dipropionate, budesonide,fluticasone propionate, ciclesonide or mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9and MMP-12.

The present invention still further relates to the combination of acompound of the invention together with modulators of chemokine receptorfunction such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4,CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family);CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1for the C-X3-C family.

The present invention still further relates to the combination of acompound of the invention together with a cytokine or modulator ofcytokine function, including alpha-, beta-, and gamma-interferon;interleukins (IL) including IL1 to 15, and interleukin antagonists orinhibitors, including agents which act on cytokine signalling pathways.

The present invention still further relates to the combination of acompound of the invention together with an immunoglobulin (Ig) or Igpreparation or an antagonist or antibody modulating Ig function such asanti-IgE (omalizumab).

The present invention further relates to the combination of a compoundof the invention and another systemic or topically-appliedanti-inflammatory agent, such as thalidomide or a derivative thereof, aretinoid, dithranol or calcipotriol.

The present invention further relates to the combination of a compoundof the invention together with an antibacterial agent such as apenicillin derivative, a tetracycline, a macrolide, a beta-lactam, afluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviralagent including acyclovir, famciclovir, valaciclovir, ganciclovir,cidofovir, amantadine, rimantadine, ribavirin, zanamavir andoseltamavir; a protease inhibitor such as indinavir, nelfinavir,ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitorsuch as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; ora non-nucleoside reverse transcriptase inhibitor such as nevirapine orefavirenz.

A compound of the invention can also be used in combination with anexisting therapeutic agent for the treatment of cancer, for examplesuitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof,as used in medical oncology, such as an alkylating agent (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan or a nitrosourea); an antimetabolite (forexample an antifolate such as a fluoropyrimidine like 5-fluorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine or paclitaxel); an antitumour antibiotic (for example ananthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); anantimitotic agent (for example a vinca alkaloid such as vincristine,vinblastine, vindesine or vinorelbine, or a taxoid such as taxol ortaxotere); or a topoisomerase inhibitor (for example anepipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecanor a camptothecin);(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen,toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogenreceptor down regulator (for example fulvestrant), an antiandrogen (forexample bicalutamide, flutamide, nilutamide or cyproterone acetate), aLHRH antagonist or LHRH agonist (for example goserelin, leuprorelin orbuserelin), a progestogen (for example megestrol acetate), an aromataseinhibitor (for example as anastrozole, letrozole, vorazole orexemestane) or an inhibitor of 5α-reductase such as finasteride;(iii) an agent which inhibits cancer cell invasion (for example ametalloproteinase inhibitor like marimastat or an inhibitor of urokinaseplasminogen activator receptor function);(iv) an inhibitor of growth factor function, for example: a growthfactor antibody (for example the anti-erbb2 antibody trastuzumab, or theanti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor,a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, aninhibitor of the epidermal growth factor family (for example an EGFRfamily tyrosine kinase inhibitor such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) or6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), an inhibitor of the platelet-derived growth factor family,or an inhibitor of the hepatocyte to growth factor family;(v) an antiangiogenic agent such as one which inhibits the effects ofvascular endothelial growth factor (for example the anti-vascularendothelial cell growth factor antibody bevacizumab, a compounddisclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or acompound that works by another mechanism (for example linomide, aninhibitor of integrin αvβ3 function or an angiostatin);(vi) a vascular damaging agent such as combretastatin A4, or a compounddisclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO02/04434 or WO 02/08213;(vii) an agent used in antisense therapy, for example one directed toone of the targets listed above, such as ISIS 2503, an anti-rasantisense;(viii) an agent used in a gene therapy approach, for example approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy;or(ix) an agent used in an immunotherapeutic approach, for example ex-vivoand in-vivo approaches to increase the immunogenicity of patient tumourcells, such as transfection with cytokines such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches to decrease T-cell anergy, approaches using transfectedimmune cells such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

-   -   The present invention will be further explained by reference to        the following illustrative examples.

EXPERIMENTAL

Unless otherwise stated organic solutions were dried over magnesiumsulphate. RPHPLC means reversed phase preparative HPLC using WatersSymmetry C8, Xterra, or Phenomenex Gemini columns using acetonitrile andeither aqueous ammonium acetate, ammonia, formic acid or trifluoroaceticacid as buffer where appropriate. Column chromatography was carried outon silica gel. Treating with SCX means the mixture was absorbed on SCXand eluted with an appropriate solvent such as methanol or acetonitrilethen the free base product eluted with aqueous ammonia/methanol.

The present invention will be further explained by reference to thefollowing illustrative examples.

The following abbreviations are used;

EtOAc ethyl acetateDCM dichloromethane

NMP N-methylpyrrolidine NBS N-bromosuccinamide DMF N,N-dimethylformamide

DMSO dimethylsulfoxideTHF tetrahydrofuranTFA trifluoroacetic acidmcpba 3-chloroperoxybenzoic acid (Aldrich 77% max)rt room temperatureh hoursmin minutesM molarMS mass spectrometryAPCI atmospheric pressure chemical ionisationNMR nuclear magnetic resonanceHCl hydrochloric acidBOC tertiary-butoxycarbonylHOBt 1-hydroxybenzotriazoleEDC 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochlorideHATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphonate

Unless otherwise stated organic solutions were dried over magnesiumsulphate. RPHPLC denotes Reverse Phase Preparative High PerformanceLiquid Chromatography using Waters Symmetry C8, Xterra or PhenomenexGemini columns using acetonitrile and either aqueous ammonium acetate,ammonia, formic acid or trifluoroacetic acid as buffer whereappropriate. Column chromatography was carried out on silica gel.

Example 16-Amino-2-butoxy-9-(3-pyrrolidin-1-ylpropyl)-7,9-dihydro-8H-purin-8-one

(i) 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolvedin 7N-aqueous ammonia in MeOH (500 ml) and heated at 100° C. in a sealedflask for 6 h. The reaction mixture was cooled to rt and left overnight.Filtration afforded the subtitle compound. Yield 40 g.

¹H NMR δ (CDCl₃) 8.02 (1H, s), 5.94 (2H, brs), 5.71 (1H, dd), 4.15-4.22(1H, m), 3.75-3.82 (1H, m), 1.27-2.12 (6H, m).

(ii) 2-Butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

The product from step (i) (40 g) was dissolved in 19% (w/w)-sodiumbutoxide in butanol (250 ml). The reaction mixture was stirred underreflux for 6 h. The resultant suspension was cooled to rt, diluted withwater and extracted with diethyl ether. The combined organic phase waswashed with water, dried and concentrated in vacuo. The subtitlecompound was crystallised from diethyl ether/isohexane (1/1, 300 ml) andobtained by filtration. Yield 19 g.

¹H NMR δ (CDCl₃) 7.87 (1H, s), 5.56-5.68 (3H, m), 4.31-4.35 (2H, t),4.14-4.17 (1H, m), 3.76-3.80 (1H, m), 1.49-2.08 (10H, m), 0.98 (3H, t).

(iii) 8-Bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl) 9H-purin-6-amine

The product from step (ii) (30 g) was dissolved in dry dichloromethane(200 ml). The solution was stirred at rt whilst NBS (27 g) was addedportionwise. The mixture was stirred at rt overnight. 20% (w/v)-Sodiumsulfate (200 ml) was added and the separated aqueous phase extractedwith DCM. The combined organic phase was washed with saturated sodiumhydrogen carbonate solution and brine. After concentration in vacuo, theresidue was dissolved in ethyl acetate, washed with water, brine anddried. The solution was filtered through silica gel and concentrated invacuo. The residue was triturated with diethyl ether and isohexane (1/1,200 ml) then filtered to give the subtitle compound (26 g). The filtratewas concentrated in vacuo and the residue purified by columnchromatography (ethyl acetate/isohexane) to give a further 2.5 g ofproduct. The solids were combined to give the subtitle compound as ayellow solid. Yield 28.5 g. mp 148-50° C.

¹H NMR δ (CDCl₃) 5.59-5.64 (3H, m), 4.32 (2H, m), 4.17 (1H, m), 3.74(1H, m), 3.08 (1H, m), 2.13 (1H, d), 1.48-1.83 (8H, m), 0.98 (3H, t).

(iv) 2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl) 9H-purin-6-amine

Sodium (3.7 g) was added to absolute MeOH (400 ml) under a nitrogenatmosphere. To this solution was added the product from step (iii) (28.5g) and the mixture was stirred at 65° C. for 9 h. The mixture wasconcentrated in vacuo and 500 ml of water added. The aqueous phase wasextracted with ethyl acetate, washed with brine and dried. The subtitlecompound was obtained after crystallisation from diethyl ether. Yield14.2 g.

¹H NMR δ (CDCl₃) 5.51 (1H, dd), 5.28 (2H, brs), 4.29 (2H, t), 4.11-4.14(4H, m), 3.70 (1H, m), 2.76-2.80 (1H, m), 2.05 (1H, d), 1.47-1.81 (8H,m), 0.97 (3H, t).

(v) 2-Butoxy-8-methoxy-9H-purin-6-amine, TFA salt

The product from step (iv) (24 g) was dissolved in absolute MeOH (300ml) and 30 ml of TFA was added. The reaction mixture was stirred at rtfor 3 days and concentrated in vacuo. The subtitle compound was obtainedas a white crystalline solid after trituration with MeOH/ethyl acetate.Yield 21 g.

¹H NMR δ (CD₃OD) 4.48 (2H, t), 4.15 (3H, s), 1.80 (2H, quintet), 1.50(2H, sextet), 0.99 (3H, t).

(vi) 9-(3-Chloropropyl)-2-butoxy-8-methoxy-9H-purin-6-amine

The product of step (v) (50 g) was added in portions over 10 minutes toa rapidly stirred mixture of potassium carbonate (60 g) and1-bromo-3-chloropropane (21 ml) in DMF (400 ml) at rt and the mixturestirred for 3 h. The mixture was diluted with water and extracted withethyl acetate. The combined extracts were washed with water and dried.The crude product was recrystallised from acetonitrile. Yield 29.83 g.

MS:ESI (+ve): 314

(vii) 6-Amino-9-(3-chloropropyl)-2-butoxy-7,9-dihydro-8H-purin-8-one

The product of step (vi) (29.8 g) was dissolved in MeOH (60 ml) andtreated with 4M hydrogen chloride in dioxane (60 ml). The mixture wasstirred at rt for 2 hours, cooled to 0° C. and neutralised with 3.5%aqueous ammonia solution. The solid was filtered off, washed with waterthen MeOH and dried Yield 27.2 g.

¹H NMR 6 (DMSO-d₆) 9.88 (1H, s), 6.41 (2H, t), 4.15 (2H, t), 3.80 (2H,t), 3.65 (2H, t), 2.14-2.07 (2H, m), 1.68-1.61 (2H, m), 1.43-1.34 (2H,m), 0.92 (3H, t).

(viii)6-Amino-2-butoxy-9-(3-pyrrolidin-1-ylpropyl)-7,9-dihydro-8H-purin-8-one

The product from step (vii) (0.15 g) was dissolved in DMSO (2 mL) andpyrrolidine (0.18 g) was added. The reaction mixture was stirred at rtfor 16 h. The reaction mixture was filtered through a filter disc andpurified via RP-prep-HPLC to give title compound (0.044 g).

¹H NMR δ (DMSO-d₆) 9.83 (1H, s), 6.37 (2H, s), 4.15 (2H, t), 3.71 (2H,t), 2.41-2.30 (6H, m), 1.84-1.73 (2H, m), 1.69-1.58 (6H, m), 1.43-1.32(2H, m), 0.92 (3H, t)

MS:ESI (+ve): 335

Examples 2-4 were made by the same method as example 1 using theappropriate amine:

Example 21-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N,N-dimethyl-L-prolinamide

¹H NMR 6 (DMSO-d₆) 9.82 (1H, s), 6.38 (2H, s), 4.14 (2H, t), 3.82-3.68(1H, m), 3.68-3.54 (1H, m), 3.48-3.35 (1H, m), 3.10-2.97 (4H, m), 2.77(3H, s), 2.35-2.21 (4H, m), 2.04-1.91 (2H, m), 1.80-1.58 (5H, m),1.45-1.31 (2H, m), 0.92 (3H, t)

MS:APCI (+ve): 406

Example 36-Amino-2-butoxy-9-{3-[(25)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR 6 (DMSO-d₆) 9.81 (1H, s), 6.37 (2H, s), 4.15 (2H, t), 3.77-3.57(2H, m), 3.30-3.23 (1H, m), 3.19 (3H, s), 3.11-2.98 (2H, m), 2.86-2.74(1H, m), 2.48-2.41 (1H, m), 2.30-2.18 (1H, m), 2.09-1.97 (1H, m),1.84-1.72 (3H, m), 1.69-1.55 (4H, m), 1.47-1.33 (3H, m), 0.92 (3H, t)

MS:APCI (+ve): 379

Example 4N²-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N¹,N¹,N²-trimethylglyeinamide

¹H NMR δ (DMSO-d₆) 9.83 (1H, s), 6.38 (2H, s), 4.14 (2H, t), 3.68 (2H,t), 3.13 (2H, s), 3.00 (3H, s), 2.78 (3H, s), 2.39 (2H, t), 2.18 (3H,s), 1.82-1.72 (2H, m), 1.69-1.58 (2H, m), 1.44-1.33 (2H, m), 0.91 (3H,t)

MS:APCI (+ve): 380

Example 51-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]pyrrolidine-2,5-dione

The product from example 1 step (vii) (0.15 g) was dissolved in DMSO (2mL) and succinimide (0.25 g) and potassium carbonate (0.07 g) was added.The reaction mixture stirred at 60° C. for 16 h. The reaction mixturewas filtered through a filter disc and purified via RP-prep-HPLC to givetitle the compound (0.065 g)

¹H NMR 8 (DMSO-d₆) 6.41 (2H, s), 4.14 (2H, t), 3.66 (2H, t), 3.40-3.33(2H, m), 2.58 (4H, s), 1.93-1.82 (2H, m), 1.69-1.58 (2H, m), 1.44-1.34(2H, m), 0.92 (3H, t)

MS:ESI (+ve): 363

Examples 6 and 7 were made by the same method as example 5 using theappropriate amine:

Example 66-Amino-2-butoxy-9-(3-{[(1S)-2-methoxy-1-methylethyl]amino}propyl)-7,9-dihydro-8H-purin-8-one

¹H NMR 6 (DMSO-d₆) 6.40 (2H, s), 4.15 (2H, t), 3.70 (2H, t), 3.31 (3H,s), 3.21 (3H, s), 3.19-3.04 (2H, m), 2.74-2.62 (1H, m), 1.79-1.56 (4H,m), 1.45-1.31 (2H, m), 0.96-0.82 (6H, m)

MS:ESI (+ve): 353

Example 76-Amino-2-butoxy-9-{3-[methyl-(2-morpholin-4-yl-2-oxo-ethyl)-amino]-propyl}-7,9-dihydro-purin-8-one

¹H NMR δ (DMSO-d₆) 9.83 (1H, s), 6.38 (2H, s), 4.14 (2H, t), 3.73-3.60(2H, m), 3.60-3.47 (5H, m), 3.45-3.37 (2H, m), 3.12 (2H, d), 2.41-2.24(3H, m), 2.17 (3H, s), 1.84-1.72 (2H, m), 1.69-1.56 (2H, m), 1.44-1.32(2H, m), 0.91 (3H, t)

MS:ESI (+ve): 422

Example 8 Biological Assay

Human TLR7 assay

Recombinant human TLR7 was stably expressed in a HEK293 cell linealready stably expressing the pNiFty2-SEAP reporter plasmid; integrationof the reporter gene was maintained by selection with the antibioticzeocin. The most common variant sequence of human TLR7 (represented bythe EMBL sequence AF240467) was cloned into the mammalian cellexpression vector pUNO and transfected into this reporter cell-line.Transfectants with stable expression were selected using the antibioticblasticidin. In this reporter cell-line, expression of secreted alkalinephosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promotercomprising five NFkB sites combined with the proximal ELAM-1 promoter.TLR signaling leads to the translocation of NFkB and to activation ofthe promoter results in expression of the SEAP gene. TLR⁷-specificactivation was assessed by determining the level of SEAP producedfollowing overnight incubation of the cells at 37° C. with the standardcompound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO).Concentration dependent induction of SEAP production by compounds wasexpressed as the concentration of compound which produced half of the ismaximal level of SEAP induction for that compound (pEC₅₀)

Compound of Example: 1 pEC₅₀ 6.4 2 pEC₅₀ 5.5 3 pEC₅₀ 5.6 4 pEC₅₀ 6.6

1. An adenine compound represented by Formula (I):

wherein R¹ represents hydrogen, hydroxyl, C₁-C₆ alkoxy, C₂-C₅alkoxycarbonyl, or a C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl or C₃-C₈ cycloalkylgroup, wherein any available carbon atom in each group is optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₅ alkoxycarbonyl, amino, mono or di-C₁-C₆ alkylamino; Y¹represents a single bond or C₁-C₆ alkylene; X¹ represents a single bondor an oxygen or sulphur atom, sulphinyl, sulphonyl or NR⁴ where R⁴ ishydrogen or C₁₋₆alkyl; provided that when R¹ is hydroxyl, C₁₋₆alkoxy orC₂-C₅ alkoxycarbonyl and X¹ is oxygen, Y¹ is other than a single bond; Lis a bond or a straight or branched C₁₋₆alkylene group, wherein up to 3carbon atoms within the alkylene group may be replaced by oxygen,sulfur, SO, SO₂, carbonyl or NR⁵ wherein R⁵ is hydrogen or C₁₋₆alkyl;and R² is either a saturated or partially unsaturated 4-8 memberedheterocycle comprising 1 or 2 hetero atoms selected from nitrogen,oxygen and sulphur, provided that at least one of the heteroatoms isnitrogen, which heterocycle is optionally substituted by one or moregroups selected from halogen, hydroxyl, oxo, C₁₋₆alkoxy,C₂₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulfinyl or an C₁₋₆ alkyl group whereinfrom 1 to 3 carbon atoms are optionally replaced by oxygen, sulphur, SO,SO₂, carbonyl or a group NR³ where R³ is hydrogen or C₁₋₆alkyl; or R² isa group of sub formula (i)

where R⁶ is hydrogen or C₁₋₆alkyl; R⁷ is hydrogen, or C₁₋₆alkyl; R⁸ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, a C₆-C₁₀ aryl,C₅-C₁₀ heteroaryl, C₃-C₈ cycloalkyl or a 3-8 membered saturated orpartially saturated heterocyclic ring wherein each group may beoptionally substituted by one or more groups selected from halogen,cyano, S(O)_(m)R¹⁰, OR¹⁰, C(O)R¹⁰, CO₂R¹⁰, OC(O)R¹⁰, SO₂NR¹¹R¹²,CONR¹¹R¹², NR¹¹R¹², NR¹¹SO₂R¹⁰, NR¹¹CO₂R¹⁰, NR¹¹COR¹⁰, where any C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl groups R⁸ mayalso be optionally substituted by one or more C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, a 3-8 membered saturated or partially saturated heterocyclicring or C₃-C₈ cycloalkyl groups and where any C₆-C₁₀ aryl or C₅-C₁₀heteroaryl groups R⁸ may also be optionally substituted by one or moreC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl groups,and where any C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl group, a C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl or 3-8 memberedsaturated or partially saturated heterocyclic ring substituents areoptionally substituted by one or more groups independently selected fromhalogen, cyano, S(O)_(m)R¹³, OR¹³, C(O)R¹³, CO₂R¹³, OC(O)R¹³,SO₂NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴R¹⁵, NR¹³SO₂R¹³, NR¹⁴CO₂R¹³ or NR¹⁴COR¹³groups; or R⁷ and R⁸ may be combined together with adjacent carbon atomto form a 3-8 membered saturated carbocycle or a 3-8 membered saturatedor partially saturated heterocycle optionally substituted by one or moregroups independently selected from halogen, cyano, S(O)_(m)R¹³, OR¹³,C(O)R¹³, CO₂R¹³, OC(O)R¹³, SO₂NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴R¹⁵, NR¹³SO₂R¹³,NR¹⁴CO₂R¹³ or NR¹⁴COR¹³ groups; R⁹ is hydrogen, S(O)_(m)R¹⁶, C(O)R¹⁶,SO₂NR¹⁷R¹⁸, CONR¹⁷R¹⁸, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₃-C₈ cycloalkyl group, the latter four groups being optionallysubstituted by one or more substituents independently selected fromhalogen, cyano, S(O)_(m)R¹⁹, OR¹⁹, C(O)R¹⁹, OC(O)R¹⁹, CO₂R¹⁹,SO₂NR²⁰R²¹, CONR²⁰R²¹, NR²⁰R²¹, NR²⁰SO₂R¹⁹, NR²⁰CO₂R¹⁹ or NR²⁰COR¹⁹; mis 0, 1 or 2; provided that when R⁸ is a C₆-C₁₀ aryl or a C₅-C₁₀heteroaryl, R⁹ is not hydrogen or unsubstituted C₁-C₆ alkyl, andprovided that when R⁷ and R⁹ are hydrogen or C₁-C₆ alkyl, then R⁸ isother than C₁-C₆ alkyl mono-substituted by C₆-C₁₀ aryl or a C₅-C₁₀heteroaryl; R¹⁰, R¹³, R¹⁶ and R¹⁹ are independently selected fromhydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃-C₈ cycloalkyl, aC₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group, which may be optionallysubstituted on any available carbon atom by one or more groups selectedfrom halogen, hydroxyl, cyano, C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulphonyl, carboxy, C₁₋₆alkylcarbonyloxy, sulphamoyl,C₁₋₆alkylsulphamoyl, di-C₁₋₆alkylsulphamoyl, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, amino, C₁₋₆alkylamino ordi-C₁₋₆alkylamino; and R¹¹, R¹², R¹⁴, R¹⁵, R¹⁷, R¹⁸, R²⁰ or R²¹ areindependently selected from hydrogen, C-₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃-C₈ cycloalkyl, a C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group,which may be optionally substituted on any available carbon atom by oneor more groups selected from halogen, hydroxyl, cyano, C₁₋₆alkoxy,mercapto, C₁₋₆alkylthio, C₁₋₆alkylsulphonyl, carboxy,C₁₋₆alkylcarbonyloxy, sulphamoyl, C₁₋₆alkylsulphamoyl,di-C₁₋₆alkylsulphamoyl, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, amino, C₁₋₆alkylamino or di-C₁₋₆alkylamino; orR¹¹ and R¹², R¹⁴ and R¹⁵, R¹⁷ and R¹⁸ or R²⁰ and R²¹ together with thenitrogen atom to which they are attached form a 3- to 8-memberedsaturated heterocyclic ring comprising a ring nitrogen atom andoptionally one or more further heteroatoms independently selected fromnitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring beingoptionally substituted by one or more substituents independentlyselected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃-C₈ cycloalkyl,halogen, hydroxyl, cyano, C₁₋₆alkoxy, C₁₋₆alkylthio,C₁₋₆(alkylsulphonyl, sulphamoyl, C₁₋₆alkylsulphamoyl,di-C₁₋₆alkylsulphamoyl, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, amino, C₁₋₆alkylamino, di-C₁₋₆alkylamino, amido,or a group NR³⁴CO₂R³⁵ or NR³⁴COR³⁵ where R³⁴ and R³⁵ are independentlyselected from hydrogen and C₁₋₆alkyl; or a pharmaceutically acceptablesalt thereof.
 2. An adenine compound represented by Formula (I):

wherein R¹ represents hydrogen, hydroxyl, C₁-C₆ alkoxy, C₂-C₅alkoxycarbonyl, or a C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl or C₃-C₈ cycloalkylgroup, wherein any available carbon atom in each group is optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₅ alkoxycarbonyl, amino, mono or di-C₁-C₆ alkylamino; Y¹represents a single bond or C₁-C₆ alkylene; X¹ represents a single bondor an oxygen or sulphur atom, sulphinyl, sulphonyl or NR⁴ where R⁴ ishydrogen or C₁₋₆alkyl; provided that when R¹ is hydroxyl, C₁₋₆alkoxy orC₂-C₅ alkoxycarbonyl and X¹ is oxygen, Y¹ is other than a single bond; Lis a bond or a straight or branched C₁₋₆alkylene group, wherein up to 3carbon atoms within the alkylene group may be replaced by oxygen,sulfur, SO, SO₂, carbonyl or NR⁵ wherein R⁵ is hydrogen or C₁₋₆alkyl;and R² is either a saturated or partially unsaturated 4-8 memberedheterocycle comprising 1 or 2 hetero atoms selected from nitrogen,oxygen and sulphur, provided that at least one of the heteroatoms isnitrogen, which heterocycle is optionally substituted by one or moregroups selected from halogen, hydroxyl, oxo, C₁₋₆alkoxy,C₂₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, C₁₋₆alkylsulfinyl or an C₁₋₆ alkyl group whereinfrom 1 to 3 carbon atoms are optionally replaced by oxygen, sulphur, SO,SO₂, carbonyl or a group NR³ where R³ is hydrogen or C₁₋₆alkyl; or R² isa group of sub formula (i)

where R⁶ is hydrogen or C₁₋₆alkyl; R⁷ is hydrogen, or C₁₋₆alkyl; R⁸ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, a C₆-C₁₀ aryl,C₅-C₁₀ heteroaryl, C₃-C₈ cycloalkyl or a 3-8 membered saturated orpartially saturated heterocyclic ring wherein each group may beoptionally substituted by one or more groups selected from halogen,cyano, S(O)_(m)R¹⁰, OR¹⁰, C(O)R¹⁰, CO₂R¹⁰, OC(O)R¹⁰, SO₂NR¹¹R¹²,CONR¹¹R¹², NR¹¹R¹², NR¹¹SO₂R¹⁰, NR¹¹CO₂R¹⁰, NR¹¹COR¹⁰, where any C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl groups R⁸ mayalso be optionally substituted by one or more C₆-C₁₀ aryl, C₈-C₁₀heteroaryl, a 3-8 membered saturated or partially saturated heterocyclicring or C₃-C₈ cycloalkyl groups and where any C₆-C₁₀ aryl or C₅-C₁₀heteroaryl groups R⁸ may also be optionally substituted by one or moreC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl groups,and where any C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl group, a C₆-C₁₀ aryl, C₅-C₁₀ heteroaryl or 3-8 memberedsaturated or partially saturated heterocyclic ring substituents areoptionally substituted by one or more groups independently selected fromhalogen, cyano, S(O)_(m)R¹³, OR¹³, C(O)R¹³, CO₂R¹³, OC(O)R¹³,SO₂NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴R¹⁵, NR¹³SO₂R¹³, NR¹⁴CO₂R¹³ or NR¹⁴COR¹³groups; or R⁷ and R⁸ may be combined together with adjacent carbon atomto form a 3-8 membered saturated carbocycle or a 3-8 membered saturatedor partially saturated heterocycle optionally substituted by one or moregroups independently selected from halogen, cyano, S(O)_(m)R¹³, OR¹³,C(O)R¹³, CO₂R¹³, OC(O)R¹³, SO₂NR¹⁴R¹⁵, CONR¹⁴R¹⁵, NR¹⁴R¹⁵, NR¹³SO₂R¹³,NR¹⁴CO₂R¹³ or NR¹⁴COR¹³ groups; R⁹ is hydrogen, S(O)_(m)R¹⁶, C(O)R¹⁶,SO₂NR¹⁷R¹⁸, CONR¹⁷R¹⁸, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₃-C₈ cycloalkyl group, the latter four groups being optionallysubstituted by one or more substituents independently selected fromhalogen, cyano, S(O)_(m)R¹⁹, OR¹⁹, C(O)R¹⁹, OC(O)R¹⁹, CO₂R¹⁹,SO₂NR²⁰R²¹, CONR²⁰R²¹, NR²⁰R²¹, NR²⁰SO₂R¹⁹, NR²⁰CO₂R¹⁹ or NR²⁰COR¹⁹; mis 0, 1 or 2; provided that when R⁸ is a C₆-C₁₀ aryl or a C₅-C₁₀heteroaryl, R⁹ is not hydrogen or unsubstituted C₁-C₆ alkyl, andprovided that when R⁷ and R⁹ are hydrogen or C₁-C₆ alkyl, then R⁸ isother than C₁-C₆ alkyl mono-substituted by C₆-C₁₀ aryl or a C₅-C₁₀heteroaryl; R¹⁰, R¹³, R¹⁶ and R¹⁹ are independently selected fromhydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃-C₈ cycloalkyl, aC₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group, which may be optionallysubstituted on any available carbon atom by one or more groups selectedfrom halogen, hydroxyl, cyano, C₁₋₆alkoxy, mercapto, C₁₋₆alkylthio,C₁₋₆alkylsulphonyl, carboxy, C₁₋₆alkylcarbonyloxy, sulphamoyl,C₁₋₆alkylsulphamoyl, di-C₁₋₆alkylsulphamoyl, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, amino, C₁₋₆alkylamino ordi-C₁₋₆alkylamino; and R¹¹, R¹², R¹⁴, R¹⁵, R¹⁷, R¹⁸, R²⁰ or R²¹ areindependently selected from hydrogen, C-₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃-C₈ cycloalkyl, a C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group,which may be optionally substituted on any available carbon atom by oneor more groups selected from halogen, hydroxyl, cyano, C₁₋₆alkoxy,mercapto, C₁₋₆alkylthio, C₁₋₆alkylsulphonyl, carboxy,C₁₋₆alkylcarbonyloxy, sulphamoyl, C₁₋₆alkylsulphamoyl,di-C₁₋₆alkylsulphamoyl, carbamoyl, C₁₋₆alkylcarbamoyl,di-C₁₋₆alkylcarbamoyl, amino, C₁₋₆alkylamino or di-C₁₋₆alkylamino; orR¹¹ and R¹², R¹⁴ and R¹⁵, R¹⁷ and R¹⁸ or R²⁰ and R²¹ together with thenitrogen atom to which they are attached form a 3- to 8-memberedsaturated heterocyclic ring comprising a ring nitrogen atom andoptionally one or more further heteroatoms independently selected fromnitrogen, oxygen, sulphur and sulphonyl, the heterocyclic ring beingoptionally substituted by one or more substituents independentlyselected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃-C₈ cycloalkyl,halogen, hydroxyl, cyano, C₁₋₆alkoxy, C₁₋₆alkylthio, C₁₋₆alkylsulphonyl,sulphamoyl, C₁₋₆alkylsulphamoyl, di-C₁₋₆alkylsulphamoyl, carbamoyl,C₁₋₆alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, amino, C₁₋₆alkylamino,di-C₁₋₆alkylamino, amido, or a group NR³⁴CO₂R³⁵ or NR³⁴COR³⁵ where R³⁴and R³⁵ are independently selected from hydrogen and C₁₋₆alkyl; providedthat when R¹ represents a hydrogen atom, Y¹ represents a linear C₄alkylene group, X¹ represents an oxygen atom and L represents a C₂alkylene group, then R² does not represent a 2-piperidinyl or4-amino-1-piperidinyl group; or a pharmaceutically acceptable saltthereof.
 3. A compound according to claim 1 wherein Y¹ is unsubstitutedC₁₋₆alkylene and R¹ is hydrogen.
 4. A compound according to claim 1wherein X¹ is oxygen.
 5. A compound according to claim 1 wherein L is aC₁₋₆alkylene group wherein up to 2 carbon atoms within the alkylenegroup of L may be replaced by oxygen, sulfur, SO, SO₂, carbonyl or NR⁵where R⁵ is hydrogen or C₁₋₆alkyl.
 6. A compound according to claim 1 orclaim 2 wherein R² is a saturated or partially unsaturated 4-8 memberedheterocycle comprising 1 or 2 hetero atoms selected from nitrogen,oxygen and sulphur, provided that at least one of the heteroatoms isnitrogen, which may be optionally substituted as defined in claim 1 orclaim
 2. 7. A compound according to claim 6 wherein R² is optionallysubstituted pyrrolidine, piperidine, piperidine, morpholine,thiomorpholine, thiomorpholine-1-oxide or thiomorpholine-1,1-dioxide. 8.A compound according to claim 1 or claim 2 wherein R² is a group of subformula (i)

where R⁶, R⁷, R⁸ and R⁹ are as defined in claim 1 or claim
 2. 9. Acompound according to claim 8 wherein R⁶ or R⁷ are independentlyhydrogen or C₁₋₃ alkyl, and R⁸ is hydrogen or C₁₋₆alkyl optionallysubstituted as defined in claim 1 or claim
 2. 10. A compound accordingto claim 9 wherein R⁸ hydrogen or a C₁₋₆ alkyl optionally substituted byone or more groups selected from C₂₋₅ alkoxycarbonyl, carboxy, hydroxy,amino optionally substituted by one or two C₁₋₆ alkyl groups which maybe the same or different, carbamoyl optionally substituted by one or twoC₁₋₆ alkyl groups which may be the same or different, 6-10 membered aryloptionally substituted by halogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, or amino optionally substituted by oneor two C₁₋₆ alkyl groups which may be the same or different
 11. Acompound according to claim 8 wherein R⁹ is hydrogen or a groupCONR¹⁷R¹⁸ where R¹⁷ and R¹⁸ are as defined in claim 1 or claim
 2. 12. Acompound according to claim 1 which is selected from:6-Amino-2-butoxy-9-(3-pyrrolidin-1-ylpropyl)-7,9-dihydro-8H-purin-8-one;1-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N,N-dimethyl-L-prolinamide;6-Amino-2-butoxy-9-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}-7,9-dihydro-8H-purin-8-one;N²-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]-N¹,N¹,N²-trimethylglycinamide;1-[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl]pyrrolidine-2,5-dione;6-Amino-2-butoxy-9-(3-{[(1S)-2-methoxy-1-methylethyl]amino}propyl)-7,9-dihydro-8H-purin-8-one;and6-Amino-2-butoxy-9-{3-[methyl-(2-morpholin-4-yl-2-oxo-ethyl)-amino]-propyl}-7,9-dihydro-purin-8-one,and pharmaceutically acceptable salts thereof.
 13. A process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as defined in claim 1 which comprises either (a)reacting a compound of formula (II)

wherein Y¹, X¹, R¹ and L are as defined in claim 1, and Z is a leavinggroup, with a compound of formula (III)H—R²  (III) where R² is as defined in claim 1, or (b) reacting acompound of formula (IV)

where L, R², R¹, X¹ and Y¹ are as defined in formula (I) claim 1 and R³⁸is a C₁₋₄alkyl group, with an acid; or (c) reacting a compound offormula (VI)

where R² and L are as defined in claim 1 and Z¹ is a leaving group, witha compound of formula (VII)R¹—Y¹—X¹—H  (VII) where R¹, Y¹and X¹ are as defined in claim 1; or (d)reacting a compound of formula (XI)

where X¹, Y¹, L and R² are as defined in claim 1 with a metal alkoxide,followed by treatment with an acid; or (e) reacting a compound offormula (XIV)

where X¹, L and R² are as defined in claim 1, with a compound of formula(XV)

where R¹ and Y¹ are as defined in claim 1 and Z² is a leaving group; or(f) reacting a compound of formula (XVII)

where L and R² are as defined in claim 1, with a compound of formula(XVI)

where R¹, X¹ and Y¹ are as defined in claim 1; and optionally thereaftercarrying out one or more of the following: converting the compound offormula (I) obtained to a further compound of formula (I) removal of anyprotecting groups forming a pharmaceutically acceptable salt of thecompound.
 14. A pharmaceutical composition comprising a compound offormula (I) as claimed in claim 1 or a pharmaceutically acceptable saltthereof in association with a pharmaceutically acceptable adjuvant,diluent or carrier.
 15. A method of treating allergic or viral diseasesor cancers or for treating asthma, COPD, allergic rhinitis, allergicconjunctivitis, atopic dermatitis, cancer, hepatitis B, hepatitis C,HIV, HPV, bacterial infections and dermatosis which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof as claimed in claim 1.